1 129 167 A UNIQUE VIRULENCE GENE OCCUPIES A PRINCIPAL POSITION IN IMMUNE EVASION BY THE MALARIA PARASITE PLASMODIUM FALCIPARUM. MUTUALLY EXCLUSIVE GENE EXPRESSION, WHEREBY ONLY ONE MEMBER OF A MULTI-GENE FAMILY IS SELECTED FOR ACTIVATION, IS USED BY THE MALARIA PARASITE PLASMODIUM FALCIPARUM TO ESCAPE THE HUMAN IMMUNE SYSTEM AND PERPETUATE LONG-TERM, CHRONIC INFECTIONS. A FAMILY OF GENES CALLED VAR ENCODES THE CHIEF ANTIGENIC AND VIRULENCE DETERMINANT OF P. FALCIPARUM MALARIA. VAR GENES ARE TRANSCRIBED IN A MUTUALLY EXCLUSIVE MANNER, WITH SWITCHING BETWEEN ACTIVE GENES RESULTING IN ANTIGENIC VARIATION. WHILE RECENT WORK HAS SHED CONSIDERABLE LIGHT ON THE EPIGENETIC BASIS FOR VAR GENE ACTIVATION AND SILENCING, HOW SWITCHING IS CONTROLLED REMAINS A MYSTERY. IN PARTICULAR, SWITCHING SEEMS NOT TO BE RANDOM, BUT INSTEAD APPEARS TO BE COORDINATED TO RESULT IN TIMELY ACTIVATION OF INDIVIDUAL GENES LEADING TO SEQUENTIAL WAVES OF ANTIGENICALLY DISTINCT PARASITE POPULATIONS. THE MOLECULAR BASIS FOR THIS APPARENT COORDINATION IS UNKNOWN. HERE WE SHOW THAT VAR2CSA, AN UNUSUAL AND HIGHLY CONSERVED VAR GENE, OCCUPIES A UNIQUE POSITION WITHIN THE VAR GENE SWITCHING HIERARCHY. INDUCTION OF SWITCHING THROUGH THE DESTABILIZATION OF VAR SPECIFIC CHROMATIN USING BOTH GENETIC AND CHEMICAL METHODS REPEATEDLY LED TO THE RAPID AND EXCLUSIVE ACTIVATION OF VAR2CSA. ADDITIONAL EXPERIMENTS DEMONSTRATED THAT THESE REPRESENT "TRUE" SWITCHING EVENTS AND NOT SIMPLY DE-SILENCING OF THE VAR2CSA PROMOTER, AND THAT ACTIVATION IS LIMITED TO THE UNIQUE LOCUS ON CHROMOSOME 12. COMBINED WITH TRANSLATIONAL REPRESSION OF VAR2CSA TRANSCRIPTS, FREQUENT "DEFAULT" SWITCHING TO THIS LOCUS AND DETECTION OF VAR2CSA UNTRANSLATED TRANSCRIPTS IN NON-PREGNANT INDIVIDUALS, THESE DATA SUGGEST THAT VAR2CSA COULD PLAY A CENTRAL ROLE IN COORDINATING SWITCHING, FULFILLING A PREDICTION MADE BY MATHEMATICAL MODELS DERIVED FROM POPULATION SWITCHING PATTERNS. THESE STUDIES PROVIDE THE FIRST INSIGHTS INTO THE MECHANISMS BY WHICH VAR GENE SWITCHING IS COORDINATED AS WELL AS AN EXAMPLE OF HOW A PHARMACOLOGICAL AGENT CAN DISRUPT ANTIGENIC VARIATION IN PLASMODIUM FALCIPARUM. 2015 2 234 29 ADDICTION OF CANCER STEM CELLS TO MUC1-C IN TRIPLE-NEGATIVE BREAST CANCER PROGRESSION. TRIPLE-NEGATIVE BREAST CANCER (TNBC) IS AN AGGRESSIVE MALIGNANCY WITH LIMITED TREATMENT OPTIONS. TNBC PROGRESSION IS ASSOCIATED WITH EXPANSION OF CANCER STEM CELLS (CSCS). FEW INSIGHTS ARE AVAILABLE REGARDING DRUGGABLE TARGETS THAT DRIVE THE TNBC CSC STATE. THIS REVIEW SUMMARIZES THE LITERATURE ON TNBC CSCS AND THE COMPELLING EVIDENCE THAT THEY ARE ADDICTED TO THE MUC1-C TRANSMEMBRANE PROTEIN. IN NORMAL EPITHELIA, MUC1-C IS ACTIVATED BY LOSS OF HOMEOSTASIS AND INDUCES REVERSIBLE WOUND-HEALING RESPONSES OF INFLAMMATION AND REPAIR. HOWEVER, IN SETTINGS OF CHRONIC INFLAMMATION, MUC1-C PROMOTES CARCINOGENESIS. MUC1-C INDUCES EMT, EPIGENETIC REPROGRAMMING AND CHROMATIN REMODELING IN TNBC CSCS, WHICH ARE DEPENDENT ON MUC1-C FOR SELF-RENEWAL AND TUMORIGENICITY. MUC1-C-INDUCED LINEAGE PLASTICITY IN TNBC CSCS CONFERS DNA DAMAGE RESISTANCE AND IMMUNE EVASION BY CHRONIC ACTIVATION OF INFLAMMATORY PATHWAYS AND GLOBAL CHANGES IN CHROMATIN ARCHITECTURE. OF THERAPEUTIC SIGNIFICANCE, AN ANTIBODY GENERATED AGAINST THE MUC1-C EXTRACELLULAR DOMAIN HAS BEEN ADVANCED IN A CLINICAL TRIAL OF ANTI-MUC1-C CAR T CELLS AND IN IND-ENABLING STUDIES FOR DEVELOPMENT AS AN ANTIBODY-DRUG CONJUGATE (ADC). AGENTS TARGETING THE MUC1-C CYTOPLASMIC DOMAIN HAVE ALSO ENTERED THE CLINIC AND ARE UNDERGOING FURTHER DEVELOPMENT AS CANDIDATES FOR ADVANCING TNBC TREATMENT. ELIMINATING TNBC CSCS WILL BE NECESSARY FOR CURING THIS RECALCITRANT CANCER AND MUC1-C REPRESENTS A PROMISING DRUGGABLE TARGET FOR ACHIEVING THAT GOAL. 2022 3 1219 66 CRISPR/CAS9 GENOME EDITING REVEALS THAT THE INTRON IS NOT ESSENTIAL FOR VAR2CSA GENE ACTIVATION OR SILENCING IN PLASMODIUM FALCIPARUM. PLASMODIUM FALCIPARUM RELIES ON MONOALLELIC EXPRESSION OF 1 OF 60 VAR VIRULENCE GENES FOR ANTIGENIC VARIATION AND HOST IMMUNE EVASION. EACH VAR GENE CONTAINS A CONSERVED INTRON WHICH HAS BEEN IMPLICATED IN PREVIOUS STUDIES IN BOTH ACTIVATION AND REPRESSION OF TRANSCRIPTION VIA SEVERAL EPIGENETIC MECHANISMS, INCLUDING INTERACTION WITH THE VAR PROMOTER, PRODUCTION OF LONG NONCODING RNAS (LNCRNAS), AND LOCALIZATION TO REPRESSIVE PERINUCLEAR SITES. HOWEVER, FUNCTIONAL STUDIES HAVE RELIED PRIMARILY ON ARTIFICIAL EXPRESSION CONSTRUCTS. USING THE RECENTLY DEVELOPED P. FALCIPARUM CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEATS (CRISPR)/CAS9 SYSTEM, WE DIRECTLY DELETED THE VAR2CSA P. FALCIPARUM 3D7_1200600 (PF3D7_1200600) ENDOGENOUS INTRON, RESULTING IN AN INTRONLESS VAR GENE IN A NATURAL, MARKER-FREE CHROMOSOMAL CONTEXT. DELETION OF THE VAR2CSA INTRON RESULTED IN AN UPREGULATION OF TRANSCRIPTION OF THE VAR2CSA GENE IN RING-STAGE PARASITES AND SUBSEQUENT EXPRESSION OF THE PFEMP1 PROTEIN IN LATE-STAGE PARASITES. INTRON DELETION DID NOT AFFECT THE NORMAL TEMPORAL REGULATION AND SUBSEQUENT TRANSCRIPTIONAL SILENCING OF THE VAR GENE IN TROPHOZOITES BUT DID RESULT IN INCREASED RATES OF VAR GENE SWITCHING IN SOME MUTANT CLONES. TRANSCRIPTIONAL REPRESSION OF THE INTRONLESS VAR2CSA GENE COULD BE ACHIEVED VIA LONG-TERM CULTURE OR PANNING WITH THE CD36 RECEPTOR, AFTER WHICH REACTIVATION WAS POSSIBLE WITH CHONDROITIN SULFATE A (CSA) PANNING. THESE DATA SUGGEST THAT THE VAR2CSA INTRON IS NOT REQUIRED FOR SILENCING OR ACTIVATION IN RING-STAGE PARASITES BUT POINT TO A SUBTLE ROLE IN REGULATION OF SWITCHING WITHIN THE VAR GENE FAMILY.IMPORTANCEPLASMODIUM FALCIPARUM IS THE MOST VIRULENT SPECIES OF MALARIA PARASITE, CAUSING HIGH RATES OF MORBIDITY AND MORTALITY IN THOSE INFECTED. CHRONIC INFECTION DEPENDS ON AN IMMUNE EVASION MECHANISM TERMED ANTIGENIC VARIATION, WHICH IN TURN RELIES ON MONOALLELIC EXPRESSION OF 1 OF ~60 VAR GENES. UNDERSTANDING ANTIGENIC VARIATION AND THE TRANSCRIPTIONAL REGULATION OF MONOALLELIC EXPRESSION IS IMPORTANT FOR DEVELOPING DRUGS AND/OR VACCINES. THE VAR GENE FAMILY ENCODES THE ANTIGENIC SURFACE PROTEINS THAT DECORATE INFECTED ERYTHROCYTES. UNTIL RECENTLY, STUDYING THE UNDERLYING GENETIC ELEMENTS THAT REGULATE MONOALLELIC EXPRESSION IN P. FALCIPARUM WAS DIFFICULT, AND MOST STUDIES RELIED ON ARTIFICIAL SYSTEMS SUCH AS EPISOMAL REPORTER GENES. OUR STUDY WAS THE FIRST TO USE CRISPR/CAS9 GENOME EDITING FOR THE FUNCTIONAL STUDY OF AN IMPORTANT, CONSERVED GENETIC ELEMENT OF VAR GENES-THE INTRON-IN AN ENDOGENOUS, EPISOME-FREE MANNER. OUR FINDINGS SHED LIGHT ON THE ROLE OF THE VAR GENE INTRON IN TRANSCRIPTIONAL REGULATION OF MONOALLELIC EXPRESSION. 2017 4 3597 40 IMPLICATIONS OF VIRAL INFECTIONS AND ONCOGENESIS IN UTERINE CERVICAL CARCINOMA ETIOLOGY AND PATHOGENESIS. BACKGROUND: UTERINE CERVICAL CARCINOMA (UCC) IS THE MOST PREVALENT GYNECOLOGICAL MALIGNANCY GLOBALLY, WITH A RISING INCIDENCE IN RECENT YEARS. ACCUMULATING EVIDENCE INDICATES THAT SPECIFIC VIRAL INFECTIONS, INCLUDING HUMAN PAPILLOMAVIRUS (HPV), EPSTEIN-BARR VIRUS (EBV), HEPATITIS B AND C VIRUSES (HBV AND HCV), AND HUMAN HERPESVIRUS (HHV), MAY CONTRIBUTE TO UCC DEVELOPMENT AND PROGRESSION. UNDERSTANDING THE COMPLEX INTERPLAY BETWEEN VIRAL INFECTIONS AND UCC RISK IS CRUCIAL FOR DEVELOPING NOVEL PREVENTATIVE AND THERAPEUTIC INTERVENTIONS. METHODS: THIS COMPREHENSIVE REVIEW INVESTIGATES THE ASSOCIATION BETWEEN VIRAL INFECTIONS AND UCC RISK BY EXAMINING THE ROLES OF VARIOUS VIRAL PATHOGENS IN UCC ETIOLOGY AND PATHOGENESIS, AND POSSIBLE MOLECULAR MECHANISMS. ADDITIONALLY, WE EVALUATE CURRENT DIAGNOSTIC METHODS AND POTENTIAL THERAPEUTIC STRATEGIES TARGETING VIRAL INFECTIONS FOR UCC PREVENTION OR TREATMENT. RESULTS: THE PREVENTION OF UCC HAS BEEN SIGNIFICANTLY ADVANCED BY THE EMERGENCE OF SELF-SAMPLING FOR HPV TESTING AS A CRUCIAL TOOL, ALLOWING FOR EARLY DETECTION AND INTERVENTION. HOWEVER, AN ESSENTIAL CHALLENGE IN UCC PREVENTION LIES IN UNDERSTANDING HOW HPV AND OTHER VIRAL COINFECTIONS, INCLUDING EBV, HBV, HCV, HHV, HIV, OR THEIR CONCURRENT PRESENCE, MAY POTENTIALLY CONTRIBUTE TO UCC DEVELOPMENT. THE MOLECULAR MECHANISMS IMPLICATED IN THE ASSOCIATION BETWEEN VIRAL INFECTIONS AND CERVICAL CANCER DEVELOPMENT INCLUDE: (1) INTERFERENCE OF VIRAL ONCOGENES WITH CELLULAR REGULATORY PROTEINS, RESULTING IN UNCONTROLLED CELL PROLIFERATION AND MALIGNANT TRANSFORMATION; (2) INACTIVATION OF TUMOR SUPPRESSOR GENES BY VIRAL PROTEINS; (3) EVASION OF HOST IMMUNE RESPONSES BY VIRUSES; (4) INDUCTION OF A PERSISTENT INFLAMMATORY RESPONSE, CONTRIBUTING TO A TUMOR-PROMOTING MICROENVIRONMENT; (5) EPIGENETIC MODIFICATIONS THAT LEAD TO ABERRANT GENE EXPRESSION; (6) STIMULATION OF ANGIOGENESIS BY VIRUSES; AND (7) ACTIVATION OF TELOMERASE BY VIRAL PROTEINS, LEADING TO CELLULAR IMMORTALIZATION. ADDITIONALLY, VIRAL COINFECTIONS CAN ALSO ENHANCE ONCOGENIC POTENTIAL THROUGH SYNERGISTIC INTERACTIONS BETWEEN VIRAL ONCOPROTEINS, EMPLOY IMMUNE EVASION STRATEGIES, CONTRIBUTE TO CHRONIC INFLAMMATION, MODULATE HOST CELLULAR SIGNALING PATHWAYS, AND INDUCE EPIGENETIC ALTERATIONS, ULTIMATELY LEADING TO CERVICAL CARCINOGENESIS. CONCLUSION: RECOGNIZING THE IMPLICATIONS OF VIRAL ONCOGENES IN UCC ETIOLOGY AND PATHOGENESIS IS VITAL FOR ADDRESSING THE ESCALATING BURDEN OF UCC. DEVELOPING INNOVATIVE PREVENTATIVE AND THERAPEUTIC INTERVENTIONS REQUIRES A THOROUGH UNDERSTANDING OF THE INTRICATE RELATIONSHIP BETWEEN VIRAL INFECTIONS AND UCC RISK. 2023 5 1218 59 CRISPR INTERFERENCE OF A CLONALLY VARIANT GC-RICH NONCODING RNA FAMILY LEADS TO GENERAL REPRESSION OF VAR GENES IN PLASMODIUM FALCIPARUM. THE HUMAN MALARIA PARASITE PLASMODIUM FALCIPARUM USES MUTUALLY EXCLUSIVE EXPRESSION OF THE PFEMP1-ENCODING VAR GENE FAMILY TO EVADE THE HOST IMMUNE SYSTEM. DESPITE PROGRESS IN THE MOLECULAR UNDERSTANDING OF THE DEFAULT SILENCING MECHANISM, THE ACTIVATION MECHANISM OF THE UNIQUELY EXPRESSED VAR MEMBER REMAINS ELUSIVE. A GC-RICH NONCODING RNA (NCRNA) GENE FAMILY HAS COEVOLVED WITH PLASMODIUM SPECIES THAT EXPRESS VAR GENES. HERE, WE SHOW THAT THIS NCRNA FAMILY IS TRANSCRIBED IN A CLONALLY VARIANT MANNER, WITH PREDOMINANT TRANSCRIPTION OF A SINGLE MEMBER OCCURRING WHEN THE NCRNA IS LOCATED ADJACENT TO AND UPSTREAM OF AN ACTIVE VAR GENE. WE DEVELOPED A SPECIFIC CRISPR INTERFERENCE (CRISPRI) STRATEGY THAT ALLOWED FOR THE TRANSCRIPTIONAL REPRESSION OF ALL GC-RICH MEMBERS. A LACK OF GC-RICH NCRNA TRANSCRIPTION LED TO THE DOWNREGULATION OF THE ENTIRE VAR GENE FAMILY IN RING-STAGE PARASITES. STRIKINGLY, IN MATURE BLOOD-STAGE PARASITES, THE GC-RICH NCRNA CRISPRI AFFECTED THE TRANSCRIPTION PATTERNS OF OTHER CLONALLY VARIANT GENE FAMILIES, INCLUDING THE DOWNREGULATION OF ALL PFMC-2TM MEMBERS. WE PROVIDE EVIDENCE FOR THE KEY ROLE OF GC-RICH NCRNA TRANSCRIPTION IN VAR GENE ACTIVATION AND DISCOVERED A MOLECULAR LINK BETWEEN THE TRANSCRIPTIONAL CONTROL OF VARIOUS CLONALLY VARIANT MULTIGENE FAMILIES INVOLVED IN PARASITE VIRULENCE. THIS WORK OPENS NEW AVENUES FOR ELUCIDATING THE MOLECULAR PROCESSES THAT CONTROL IMMUNE EVASION AND PATHOGENESIS IN P. FALCIPARUMIMPORTANCEPLASMODIUM FALCIPARUM IS THE DEADLIEST MALARIA PARASITE SPECIES, ACCOUNTING FOR THE VAST MAJORITY OF DISEASE CASES AND DEATHS. THE VIRULENCE OF THIS PARASITE IS RELIANT UPON THE MUTUALLY EXCLUSIVE EXPRESSION OF CYTOADHERENCE PROTEINS ENCODED BY THE 60-MEMBER VAR GENE FAMILY. ANTIGENIC VARIATION OF THIS MULTIGENE FAMILY SERVES AS AN IMMUNE EVASION MECHANISM, ULTIMATELY LEADING TO CHRONIC INFECTION AND PATHOGENESIS. UNDERSTANDING THE REGULATION MECHANISM OF ANTIGENIC VARIATION IS KEY TO DEVELOPING NEW THERAPEUTIC AND CONTROL STRATEGIES. OUR STUDY UNCOVERS A NOVEL LAYER IN THE EPIGENETIC REGULATION OF TRANSCRIPTION OF THIS FAMILY OF VIRULENCE GENES BY MEANS OF A MULTIGENE-TARGETING CRISPR INTERFERENCE APPROACH. 2020 6 2091 47 EPIGENETIC DYSREGULATION OF VIRULENCE GENE EXPRESSION IN SEVERE PLASMODIUM FALCIPARUM MALARIA. CHRONIC INFECTIONS WITH THE HUMAN MALARIA PARASITE PLASMODIUM FALCIPARUM DEPEND ON ANTIGENIC VARIATION. P. FALCIPARUM ERYTHROCYTE MEMBRANE PROTEIN 1 (PFEMP1), THE MAJOR ERYTHROCYTE SURFACE ANTIGEN MEDIATING PARASITE SEQUESTRATION IN THE MICROVASCULATURE, IS ENCODED IN PARASITES BY A HIGHLY DIVERSE FAMILY OF VAR GENES. ANTIGENIC SWITCHING IS MEDIATED BY CLONAL VARIATION IN VAR EXPRESSION, AND RECENT IN VITRO STUDIES HAVE DEMONSTRATED A ROLE FOR EPIGENETIC PROCESSES IN VAR REGULATION. EXPRESSION OF PARTICULAR PFEMP1 VARIANTS MAY RESULT IN PARASITE ENRICHMENT IN DIFFERENT TISSUES, A FACTOR IN THE DEVELOPMENT OF SEVERE DISEASE. HERE, WE STUDY IN VIVO HUMAN INFECTIONS AND PROVIDE EVIDENCE THAT INFECTION-INDUCED STRESS RESPONSES IN THE HOST CAN MODIFY PFEMP1 EXPRESSION VIA THE PERTURBATION OF EPIGENETIC MECHANISMS. OUR WORK SUGGESTS THAT SEVERE DISEASE MAY NOT BE THE DIRECT RESULT OF AN ADAPTIVE VIRULENCE STRATEGY TO MAXIMIZE PARASITE SURVIVAL BUT THAT IT MAY INDICATE A LOSS OF CONTROL OF THE CAREFULLY REGULATED PROCESS OF ANTIGENIC SWITCHING THAT MAINTAINS CHRONIC INFECTIONS. 2012 7 4512 23 MUC1-C IN CHRONIC INFLAMMATION AND CARCINOGENESIS; EMERGENCE AS A TARGET FOR CANCER TREATMENT. CHRONIC INFLAMMATION IS A HIGHLY PREVALENT CONSEQUENCE OF CHANGES IN ENVIRONMENTAL AND LIFESTYLE FACTORS THAT CONTRIBUTE TO THE DEVELOPMENT OF CANCER. THE BASIS FOR THIS CRITICAL ASSOCIATION HAS LARGELY REMAINED UNCLEAR. THE MUC1 GENE EVOLVED IN MAMMALS TO PROTECT EPITHELIA FROM THE EXTERNAL ENVIRONMENT. THE MUC1-C SUBUNIT PROMOTES RESPONSES FOUND IN WOUND HEALING AND CANCER. MUC1-C INDUCES EMT, EPIGENETIC REPROGRAMMING, DEDIFFERENTIATION AND PLURIPOTENCY FACTOR EXPRESSION, WHICH WHEN PROLONGED IN CHRONIC INFLAMMATION PROMOTE CANCER PROGRESSION. AS DISCUSSED IN THIS REVIEW, MUC1-C ALSO DRIVES DRUG RESISTANCE AND IMMUNE EVASION, AND IS AN IMPORTANT TARGET FOR CANCER THERAPEUTICS NOW UNDER DEVELOPMENT. 2020 8 4769 33 NUCLEAR MORPHOMETRY, NUCLEOMICS AND PROSTATE CANCER PROGRESSION. PROSTATE CANCER (PCA) RESULTS FROM A MULTISTEP PROCESS. THIS PROCESS INCLUDES INITIATION, WHICH OCCURS THROUGH VARIOUS AGING EVENTS AND MULTIPLE INSULTS (SUCH AS CHRONIC INFECTION, INFLAMMATION AND GENETIC INSTABILITY THROUGH REACTIVE OXYGEN SPECIES CAUSING DNA DOUBLE-STRAND BREAKS), FOLLOWED BY A MULTISTEP PROCESS OF PROGRESSION. THESE STEPS INCLUDE SEVERAL GENETIC AND EPIGENETIC ALTERATIONS, AS WELL AS ALTERATIONS TO THE CHROMATIN STRUCTURE, WHICH OCCUR IN RESPONSE TO THE CARCINOGENIC STRESS-RELATED EVENTS THAT SUSTAIN PROLIFERATIVE SIGNALING. EVENTS SUCH AS EVADING GROWTH SUPPRESSORS, RESISTING CELL DEATH, ENABLING REPLICATIVE IMMORTALITY, INDUCING ANGIOGENESIS, AND ACTIVATING INVASION AND METASTASIS ARE READILY OBSERVED. IN ADDITION, IN CONJUNCTION WITH THESE CRITICAL DRIVERS OF CARCINOGENESIS, OTHER FACTORS RELATED TO THE ETIOPATHOGENESIS OF PCA, INVOLVING ENERGY METABOLISM AND EVASION OF THE IMMUNE SURVEILLANCE SYSTEM, APPEAR TO BE INVOLVED. IN ADDITION, WHEN CANCER SPREAD AND METASTASIS OCCUR, THE 'TUMOR MICROENVIRONMENT' IN THE BONE OF PCA PATIENTS MAY PROVIDE A WAY TO SUSTAIN DORMANCY OR SENESCENCE AND EVENTUALLY ESTABLISH A 'SEED AND SOIL' SITE WHERE PCA PROLIFERATION AND GROWTH MAY OCCUR OVER TIME. WHEN PCA IS INITIATED AND PROGRESSION ENSUES, SIGNIFICANT ALTERATIONS IN NUCLEAR SIZE, SHAPE AND HETEROCHROMATIN (DNA TRANSCRIPTION) ORGANIZATION ARE FOUND, AND KEY NUCLEAR TRANSCRIPTIONAL AND STRUCTURAL PROTEINS, AS WELL AS MULTIPLE NUCLEAR BODIES CAN LEAD TO PRECANCEROUS AND MALIGNANT CHANGES. THESE SERIES OF CELLULAR AND TISSUE-RELATED MALIGNANCY-ASSOCIATED EVENTS CAN BE QUANTIFIED TO ASSESS DISEASE PROGRESSION AND MANAGEMENT. 2012 9 6444 45 THERAPEUTIC ASPECTS OF C-MYC SIGNALING IN INFLAMMATORY AND CANCEROUS COLONIC DISEASES. COLONIC INFLAMMATION IS REQUIRED TO HEAL INFECTIONS, WOUNDS, AND MAINTAIN TISSUE HOMEOSTASIS. AS THE SEVENTH HALLMARK OF CANCER, HOWEVER, IT MAY AFFECT ALL PHASES OF TUMOR DEVELOPMENT, INCLUDING TUMOR INITIATION, PROMOTION, INVASION AND METASTATIC DISSEMINATION, AND ALSO EVASION IMMUNE SURVEILLANCE. INFLAMMATION ACTS AS A CELLULAR STRESSOR AND MAY TRIGGER DNA DAMAGE OR GENETIC INSTABILITY, AND, FURTHER, CHRONIC INFLAMMATION CAN PROVOKE GENETIC MUTATIONS AND EPIGENETIC MECHANISMS THAT PROMOTE MALIGNANT CELL TRANSFORMATION. BOTH SPORADICAL AND COLITIS-ASSOCIATED COLORECTAL CARCINOGENESIS ARE MULTI-STEP, COMPLEX PROCESSES ARISING FROM THE UNCONTROLLED PROLIFERATION AND SPREADING OF MALIGNANTLY TRANSFORMED CELL CLONES WITH THE OBVIOUS ABILITY TO EVADE THE HOST'S PROTECTIVE IMMUNITY. IN CELLS UPON DNA DAMAGE SEVERAL PROTO-ONCOGENES, INCLUDING C-MYC ARE ACTIVATED IN PARELELL WITH THE INACTIVATION OF TUMOR SUPPRESSOR GENES. THE TARGET GENES OF THE C-MYC PROTEIN PARTICIPATE IN DIFFERENT CELLULAR FUNCTIONS, INCLUDING CELL CYCLE, SURVIVAL, PROTEIN SYNTHESIS, CELL ADHESION, AND MICRO-RNA EXPRESSION. THE TRANSCRIPTIONAL PROGRAM REGULATED BY C-MYC IS CONTEXT DEPENDENT, THEREFORE THE FINAL CELLULAR RESPONSE TO ELEVATED C-MYC LEVELS MAY RANGE FROM INCREASED PROLIFERATION TO AUGMENTED APOPTOSIS. CONSIDERING PHYSIOLOGICAL INTESTINAL HOMEOSTASIS, C-MYC DISPLAYS A FUNDAMENTAL ROLE IN THE REGULATION OF CELL PROLIFERATION AND CRYPT CELL NUMBER. HOWEVER, C-MYC GENE IS FREQUENTLY DEREGULATED IN INFLAMMATION, AND OVEREXPRESSED IN BOTH SPORADIC AND COLITIS-ASSOCIATED COLON ADENOCARCINOMAS. RECENT RESULTS DEMONSTRATED THAT ENDOGENOUS C-MYC IS ESSENTIAL FOR EFFICIENT INDUCTION OF P53-DEPENDENT APOPTOSIS FOLLOWING DNA DAMAGE, BUT C-MYC FUNCTION IS ALSO INVOLVED IN AND REGULATED BY AUTOPHAGY-RELATED MECHANISMS, WHILE ITS EXPRESSION IS AFFECTED BY DNA-METHYLATION, OR HISTONE ACETYLATION. MOLECULES DIRECTLY TARGETING C-MYC, OR AGENTS ACTING ON OTHER GENES INVOLVED IN THE C-MYC PATHWAY COULD BE SELECTED FOR COMBINED REGIMENTS. HOWEVER, DUE TO ITS CONTEXT-DEPENDENT CELLULAR FUNCTION, IT IS CLINICALLY ESSENTIAL TO CONSIDER WHICH CYTOTOXIC DRUGS ARE USED IN COMBINATION WITH C-MYC TARGETED AGENTS IN VARIOUS TISSUES. INCREASING OUR KNOWLEDGE ABOUT MYC-DEPENDENT PATHWAYS MIGHT PROVIDE DIRECTION TO NOVEL ANTI-INFLAMMATORY AND COLORECTAL CANCER THERAPIES. 2016 10 6179 50 THE HUMAN MALARIA PARASITE PLASMODIUM FALCIPARUM CAN SENSE ENVIRONMENTAL CHANGES AND RESPOND BY ANTIGENIC SWITCHING. THE PRIMARY ANTIGENIC AND VIRULENCE DETERMINANT OF THE HUMAN MALARIA PARASITE PLASMODIUM FALCIPARUM IS A VARIANT SURFACE PROTEIN CALLED PFEMP1. DIFFERENT FORMS OF PFEMP1 ARE ENCODED BY A MULTICOPY GENE FAMILY CALLED VAR, AND SWITCHING BETWEEN ACTIVE GENES ENABLES THE PARASITES TO EVADE THE ANTIBODY RESPONSE OF THEIR HUMAN HOSTS. VAR GENE SWITCHING IS KEY FOR THE MAINTENANCE OF CHRONIC INFECTIONS; HOWEVER, WHAT CONTROLS SWITCHING IS UNKNOWN, ALTHOUGH IT HAS BEEN SUGGESTED TO OCCUR AT A CONSTANT FREQUENCY WITH LITTLE OR NO ENVIRONMENTAL INFLUENCE. VAR GENE TRANSCRIPTION IS CONTROLLED EPIGENETICALLY THROUGH THE ACTIVITY OF HISTONE METHYLTRANSFERASES (HMTS). STUDIES IN MODEL SYSTEMS HAVE SHOWN THAT METABOLISM AND EPIGENETIC CONTROL OF GENE EXPRESSION ARE LINKED THROUGH THE AVAILABILITY OF INTRACELLULAR S-ADENOSYLMETHIONINE (SAM), THE PRINCIPAL METHYL DONOR IN BIOLOGICAL METHYLATION MODIFICATIONS, WHICH CAN FLUCTUATE BASED ON NUTRIENT AVAILABILITY. TO DETERMINE WHETHER ENVIRONMENTAL CONDITIONS AND CHANGES IN METABOLISM CAN INFLUENCE VAR GENE EXPRESSION, P. FALCIPARUM WAS CULTURED IN MEDIA WITH ALTERED CONCENTRATIONS OF NUTRIENTS INVOLVED IN SAM METABOLISM. WE FOUND THAT CONDITIONS THAT INFLUENCE LIPID METABOLISM INDUCE VAR GENE SWITCHING, INDICATING THAT PARASITES CAN RESPOND TO CHANGES IN THEIR ENVIRONMENT BY ALTERING VAR GENE EXPRESSION PATTERNS. GENETIC MODIFICATIONS THAT DIRECTLY MODIFIED EXPRESSION OF THE ENZYMES THAT CONTROL SAM LEVELS SIMILARLY LED TO PROFOUND CHANGES IN VAR GENE EXPRESSION, CONFIRMING THAT CHANGES IN SAM AVAILABILITY MODULATE VAR GENE SWITCHING. THESE OBSERVATIONS DIRECTLY CHALLENGE THE PARADIGM THAT ANTIGENIC VARIATION IN P. FALCIPARUM FOLLOWS AN INTRINSIC, PROGRAMED SWITCHING RATE, WHICH OPERATES INDEPENDENTLY OF ANY EXTERNAL STIMULI. 2023 11 866 30 CHRONIC ACTIVATION OF MUC1-C IN WOUND REPAIR PROMOTES PROGRESSION TO CANCER STEM CELLS. THE MUCIN 1 (MUC1) GENE EMERGED IN MAMMALS TO AFFORD PROTECTION OF BARRIER EPITHELIAL TISSUES FROM THE EXTERNAL ENVIRONMENT. MUC1 ENCODES A TRANSMEMBRANE C-TERMINAL (MUC1-C) SUBUNIT THAT IS ACTIVATED BY LOSS OF HOMEOSTASIS AND INDUCES INFLAMMATORY, PROLIFERATIVE, AND REMODELING PATHWAYS ASSOCIATED WITH WOUND REPAIR. AS A CONSEQUENCE, CHRONIC ACTIVATION OF MUC1-C PROMOTES LINEAGE PLASTICITY, EPIGENETIC REPROGRAMMING, AND CARCINOGENESIS. IN DRIVING CANCER PROGRESSION, MUC1-C IS IMPORTED INTO THE NUCLEUS, WHERE IT INDUCES NF-KAPPAB INFLAMMATORY SIGNALING AND THE EPITHELIAL-MESENCHYMAL TRANSITION (EMT). MUC1-C REPRESSES GENE EXPRESSION BY ACTIVATING (I) DNA METHYLTRANSFERASE 1 (DNMT1) AND DNMT3B, (II) POLYCOMB REPRESSIVE COMPLEX 1 (PRC1) AND PRC2, AND (III) THE NUCLEOSOME REMODELING AND DEACETYLASE (NURD) COMPLEX. PRC1/2-MEDIATED GENE REPRESSION IS COUNTERACTED BY THE SWI/SNF CHROMATIN REMODELING COMPLEXES. MUC1-C ACTIVATES THE SWI/SNF BAF AND PBAF COMPLEXES IN CANCER STEM CELL (CSC) MODELS WITH THE INDUCTION OF GENOME-WIDE DIFFERENTIALLY ACCESSIBLE REGIONS AND EXPRESSED GENES. MUC1-C REGULATES CHROMATIN ACCESSIBILITY OF ENHANCER-LIKE SIGNATURES IN ASSOCIATION WITH THE INDUCTION OF THE YAMANAKA PLURIPOTENCY FACTORS AND RECRUITMENT OF JUN AND BAF, WHICH PROMOTE INCREASES IN HISTONE ACTIVATION MARKS AND OPENING OF CHROMATIN. THESE AND OTHER FINDINGS DESCRIBED IN THIS REVIEW HAVE UNCOVERED A PIVOTAL ROLE FOR MUC1-C IN INTEGRATING LINEAGE PLASTICITY AND EPIGENETIC REPROGRAMMING, WHICH ARE TRANSIENT IN WOUND REPAIR AND SUSTAINED IN PROMOTING CSC PROGRESSION. 2022 12 2036 33 EPIGENETIC CHANGES OF THE IMMUNE SYSTEM WITH ROLE IN TUMOR DEVELOPMENT. TUMOR DEVELOPMENT IS CLOSELY RELATED TO CHRONIC INFLAMMATION AND TO EVASION OF IMMUNE DEFENSE MECHANISMS BY NEOPLASTIC CELLS. THE MEDIATORS OF THE INFLAMMATORY PROCESS AS WELL AS PROTEINS INVOLVED IN IMMUNE RESPONSE OR IMMUNE RESPONSE EVASION CAN BE SUBJECT TO VARIOUS EPIGENETIC CHANGES SUCH AS METHYLATION, ACETYLATION, OR PHOSPHORYLATION. SOME OF THESE, SUCH AS CYTOKINE SUPPRESSORS, ARE UNDERGOING REPRESSION THROUGH EPIGENETIC CHANGES, AND OTHERS SUCH AS CYTOKINES OR CHEMOKINES ARE UNDERGOING ACTIVATION THROUGH EPIGENETIC CHANGES, BOTH MODIFICATIONS HAVING AS A RESULT TUMOR PROGRESSION. THE ACTIVATING CHANGES CAN AFFECT THE RECEPTOR MOLECULES INVOLVED IN IMMUNE RESPONSE AND THESE PROMOTE INFLAMMATION AND SUBSEQUENTLY TUMOR DEVELOPMENT WHILE THE INACTIVATING CHANGES SEEM TO BE RELATED TO THE TUMOR REGRESSION PROCESS. THE PROTEINS INVOLVED IN ANTIGEN PRESENTATION, AND, THEREFORE IN IMMUNE RESPONSE ESCAPE, SUCH AS CLASSICAL HLA PROTEINS AND RELATED APM (ANTIGEN PRESENTATION MACHINERY) WITH THEIR EPIGENETIC CHANGES CONTRIBUTE TO THE TUMOR DEVELOPMENT PROCESS, EITHER TO TUMOR PROGRESSION OR REGRESSION, DEPENDING ON THE IMMUNE EFFECTOR CELLS THAT ARE IN PLAY. 2018 13 1853 32 ELEVATED METHIONINE FLUX DRIVES PYROPTOSIS EVASION IN PERSISTER CANCER CELLS. INDUCTION OF CELL DEATH REPRESENTS A PRIMARY GOAL OF MOST ANTICANCER TREATMENTS. DESPITE THE EFFICACY OF SUCH APPROACHES, A SMALL POPULATION OF "PERSISTERS" DEVELOP EVASION STRATEGIES TO THERAPY-INDUCED CELL DEATH. WHILE PREVIOUS STUDIES HAVE IDENTIFIED MECHANISMS OF RESISTANCE TO APOPTOSIS, THE MECHANISMS BY WHICH PERSISTERS DAMPEN OTHER FORMS OF CELL DEATH, SUCH AS PYROPTOSIS, REMAIN TO BE ELUCIDATED. PYROPTOSIS IS A FORM OF INFLAMMATORY CELL DEATH THAT INVOLVES FORMATION OF MEMBRANE PORES, ION GRADIENT IMBALANCE, WATER INFLOW, AND MEMBRANE RUPTURE. HEREIN, WE INVESTIGATE MECHANISMS BY WHICH CANCER PERSISTERS RESIST PYROPTOSIS, SURVIVE, THEN PROLIFERATE IN THE PRESENCE OF TYROSINE KINASE INHIBITORS (TKI). LUNG, PROSTATE, AND ESOPHAGEAL CANCER PERSISTER CELLS REMAINING AFTER TREATMENTS EXHIBITED SEVERAL HALLMARKS INDICATIVE OF PYROPTOSIS RESISTANCE. THE INFLAMMATORY ATTRIBUTES OF PERSISTERS INCLUDED CHRONIC ACTIVATION OF INFLAMMASOME, STING, AND TYPE I INTERFERONS. COMPREHENSIVE METABOLOMIC CHARACTERIZATION UNCOVERED THAT TKI-INDUCED PYROPTOTIC PERSISTERS DISPLAY HIGH METHIONINE CONSUMPTION AND EXCESSIVE TAURINE PRODUCTION. ELEVATED METHIONINE FLUX OR EXOGENOUS TAURINE PRESERVED PLASMA MEMBRANE INTEGRITY VIA OSMOLYTE-MEDIATED EFFECTS. INCREASED DEPENDENCY ON METHIONINE FLUX DECREASED THE LEVEL OF ONE CARBON METABOLISM INTERMEDIATE S-(5'-ADENOSYL)-L-HOMOCYSTEINE, A DETERMINANT OF CELL METHYLATION CAPACITY. THE CONSEQUENT INCREASE IN METHYLATION POTENTIAL INDUCED DNA HYPERMETHYLATION OF GENES REGULATING METAL ION BALANCE AND INTRINSIC IMMUNE RESPONSE. THIS ENABLED THWARTING TKI RESISTANCE BY USING THE HYPOMETHYLATING AGENT DECITABINE. IN SUMMARY, THE EVOLUTION OF RESISTANCE TO PYROPTOSIS CAN OCCUR VIA A STEPWISE PROCESS OF PHYSICAL ACCLIMATION AND EPIGENETIC CHANGES WITHOUT EXISTING OR RECURRENT MUTATIONS. SIGNIFICANCE: METHIONINE ENABLES CANCER CELLS TO PERSIST BY EVADING PYROPTOTIC OSMOTIC LYSIS, WHICH LEADS TO GENOME-WIDE HYPERMETHYLATION THAT ALLOWS PERSISTERS TO GAIN PROLIFERATIVE ADVANTAGES. 2023 14 4409 27 MOLECULAR ANATOMY AND PATHOGENIC ACTIONS OF HELICOBACTER PYLORI CAGA THAT UNDERPIN GASTRIC CARCINOGENESIS. CHRONIC INFECTION WITH HELICOBACTER PYLORI CAGA-POSITIVE STRAINS IS THE STRONGEST RISK FACTOR FOR GASTRIC CANCER. THE CAGA GENE PRODUCT, CAGA, IS DELIVERED INTO GASTRIC EPITHELIAL CELLS VIA THE BACTERIAL TYPE IV SECRETION SYSTEM. DELIVERED CAGA THEN UNDERGOES TYROSINE PHOSPHORYLATION AT THE GLU-PRO-ILE-TYR-ALA (EPIYA) MOTIFS IN ITS C-TERMINAL REGION AND ACTS AS AN ONCOGENIC SCAFFOLD PROTEIN THAT PHYSICALLY INTERACTS WITH MULTIPLE HOST SIGNALING PROTEINS IN BOTH TYROSINE PHOSPHORYLATION-DEPENDENT AND -INDEPENDENT MANNERS. ANALYSIS OF CAGA USING IN VITRO CULTURED GASTRIC EPITHELIAL CELLS HAS INDICATED THAT THE NONPHYSIOLOGICAL SCAFFOLDING ACTIONS OF CAGA CELL-AUTONOMOUSLY PROMOTE THE MALIGNANT TRANSFORMATION OF THE CELLS BY ENDOWING THE CELLS WITH MULTIPLE PHENOTYPIC CANCER HALLMARKS: SUSTAINED PROLIFERATION, EVASION OF GROWTH SUPPRESSORS, INVASIVENESS, RESISTANCE TO CELL DEATH, AND GENOMIC INSTABILITY. TRANSGENIC EXPRESSION OF CAGA IN MICE LEADS TO IN VIVO ONCOGENIC ACTION OF CAGA WITHOUT ANY OVERT INFLAMMATION. THE IN VIVO ONCOGENIC ACTIVITY OF CAGA IS FURTHER POTENTIATED IN THE PRESENCE OF CHRONIC INFLAMMATION. SINCE HELICOBACTER PYLORI INFECTION TRIGGERS A PROINFLAMMATORY RESPONSE IN HOST CELLS, A FEEDFORWARD STIMULATION LOOP THAT AUGMENTS THE ONCOGENIC ACTIONS OF CAGA AND INFLAMMATION IS CREATED IN CAGA-INJECTED GASTRIC MUCOSA. GIVEN THAT HELICOBACTER PYLORI IS NO LONGER COLONIZED IN ESTABLISHED GASTRIC CANCER LESIONS, THE MULTISTEP NATURE OF GASTRIC CANCER DEVELOPMENT SHOULD INCLUDE A "HIT-AND-RUN" PROCESS OF CAGA ACTION. THUS, ACQUISITION OF GENETIC AND EPIGENETIC ALTERATIONS THAT COMPENSATE FOR CAGA-DIRECTED CANCER HALLMARKS MAY BE REQUIRED FOR COMPLETION OF THE "HIT-AND-RUN" PROCESS OF GASTRIC CARCINOGENESIS. 2020 15 4462 31 MOLECULAR MECHANISMS OF HBV-ASSOCIATED HEPATOCARCINOGENESIS. HEPATITIS B VIRUS (HBV) CONTRIBUTES TO HEPATOCELLULAR CARCINOMA (HCC) DEVELOPMENT THROUGH DIRECT AND INDIRECT MECHANISMS. HBV-DNA INTEGRATION INTO THE HOST GENOME OCCURS AT EARLY STEPS OF CLONAL TUMOR EXPANSION AND INDUCES BOTH GENOMIC INSTABILITY AND DIRECT INSERTIONAL MUTAGENESIS OF DIVERSE CANCER-RELATED GENES. PROLONGED EXPRESSION OF THE VIRAL REGULATORY PROTEIN HBX AND THE LARGE ENVELOPE PROTEIN DEREGULATE THE CELLULAR TRANSCRIPTION PROGRAM AND PROLIFERATION CONTROL AND SENSITIZE LIVER CELLS TO CARCINOGENIC FACTORS. EPIGENETIC CHANGES TARGETING THE EXPRESSION OF TUMOR SUPPRESSOR GENES OCCUR EARLY IN THE DEVELOPMENT OF HCC. A MAJOR ROLE IS PLAYED BY HBX THAT IS RECRUITED ON CELLULAR CHROMATIN AND MODULATES CHROMATIN DYNAMICS AT SPECIFIC GENE LOCI. COMPARED WITH TUMORS ASSOCIATED WITH OTHER RISK FACTORS, HBV-RELATED TUMORS HAVE A HIGHER RATE OF CHROMOSOMAL ALTERATIONS AND P53 INACTIVATION BY MUTATIONS, OVEREXPRESS FETAL LIVER/HEPATIC PROGENITOR CELLS GENES, AND SHOW A SPECIFIC ACTIVATION OF THE AKT PATHWAY. THE WNT/BETA-CATENIN PATHWAY IS ALSO OFTEN ACTIVATED, BUT HBV-RELATED TUMORS DISPLAY A LOW RATE OF ACTIVATING BETA-CATENIN MUTATIONS. ALL AVAILABLE EVIDENCE STRONGLY SUPPORTS THE NOTION THAT CHRONIC HBV INFECTION TRIGGERS BOTH COMMON AND ETIOLOGY-SPECIFIC ONCOGENIC PATHWAYS, THUS PLAYING A DIRECT ROLE BEYOND STIMULATION OF HOST IMMUNE RESPONSES AND CHRONIC NECROINFLAMMATORY LIVER DISEASE. 2013 16 3688 35 INFLAMMATION: GEARING THE JOURNEY TO CANCER. CHRONIC INFLAMMATION PLAYS A MULTIFACETED ROLE IN CARCINOGENESIS. MOUNTING EVIDENCE FROM PRECLINICAL AND CLINICAL STUDIES SUGGESTS THAT PERSISTENT INFLAMMATION FUNCTIONS AS A DRIVING FORCE IN THE JOURNEY TO CANCER. THE POSSIBLE MECHANISMS BY WHICH INFLAMMATION CAN CONTRIBUTE TO CARCINOGENESIS INCLUDE INDUCTION OF GENOMIC INSTABILITY, ALTERATIONS IN EPIGENETIC EVENTS AND SUBSEQUENT INAPPROPRIATE GENE EXPRESSION, ENHANCED PROLIFERATION OF INITIATED CELLS, RESISTANCE TO APOPTOSIS, AGGRESSIVE TUMOR NEOVASCULARIZATION, INVASION THROUGH TUMOR-ASSOCIATED BASEMENT MEMBRANE AND METASTASIS, ETC. INFLAMMATION-INDUCED REACTIVE OXYGEN AND NITROGEN SPECIES CAUSE DAMAGE TO IMPORTANT CELLULAR COMPONENTS (E.G., DNA, PROTEINS AND LIPIDS), WHICH CAN DIRECTLY OR INDIRECTLY CONTRIBUTE TO MALIGNANT CELL TRANSFORMATION. OVEREXPRESSION, ELEVATED SECRETION, OR ABNORMAL ACTIVATION OF PROINFLAMMATORY MEDIATORS, SUCH AS CYTOKINES, CHEMOKINES, CYCLOOXYGENASE-2, PROSTAGLANDINS, INDUCIBLE NITRIC OXIDE SYNTHASE, AND NITRIC OXIDE, AND A DISTINCT NETWORK OF INTRACELLULAR SIGNALING MOLECULES INCLUDING UPSTREAM KINASES AND TRANSCRIPTION FACTORS FACILITATE TUMOR PROMOTION AND PROGRESSION. WHILE INFLAMMATION PROMOTES DEVELOPMENT OF CANCER, COMPONENTS OF THE TUMOR MICROENVIRONMENT, SUCH AS TUMOR CELLS, STROMAL CELLS IN SURROUNDING TISSUE AND INFILTRATED INFLAMMATORY/IMMUNE CELLS GENERATE AN INTRATUMORAL INFLAMMATORY STATE BY ABERRANT EXPRESSION OR ACTIVATION OF SOME PROINFLAMMATORY MOLECULES. MANY OF PROINFLAMMATORY MEDIATORS, ESPECIALLY CYTOKINES, CHEMOKINES AND PROSTAGLANDINS, TURN ON THE ANGIOGENIC SWITCHES MAINLY CONTROLLED BY VASCULAR ENDOTHELIAL GROWTH FACTOR, THEREBY INDUCING INFLAMMATORY ANGIOGENESIS AND TUMOR CELL-STROMA COMMUNICATION. THIS WILL END UP WITH TUMOR ANGIOGENESIS, METASTASIS AND INVASION. MOREOVER, CELLULAR MICRORNAS ARE EMERGING AS A POTENTIAL LINK BETWEEN INFLAMMATION AND CANCER. THE PRESENT ARTICLE HIGHLIGHTS THE ROLE OF VARIOUS PROINFLAMMATORY MEDIATORS IN CARCINOGENESIS AND THEIR PROMISE AS POTENTIAL TARGETS FOR CHEMOPREVENTION OF INFLAMMATION-ASSOCIATED CARCINOGENESIS. 2008 17 6592 31 TUMOR-ASSOCIATED MACROPHAGES IN HEPATOCELLULAR CARCINOMA PATHOGENESIS, PROGNOSIS AND THERAPY. HEPATOCELLULAR CARCINOMA (HCC) CONSTITUTES A MAJOR HEALTH BURDEN GLOBALLY, AND IT IS CAUSED BY INTRINSIC GENETIC MUTATIONS ACTING IN CONCERT WITH A MULTITUDE OF EPIGENETIC AND EXTRINSIC RISK FACTORS. CANCER INDUCES MYELOPOIESIS IN THE BONE MARROW, AS WELL AS THE MOBILIZATION OF HEMATOPOIETIC STEM AND PROGENITOR CELLS, WHICH RESIDE IN THE SPLEEN. MONOCYTES PRODUCED IN THE BONE MARROW AND THE SPLEEN FURTHER INFILTRATE TUMORS, WHERE THEY DIFFERENTIATE INTO TUMOR-ASSOCIATED MACROPHAGES (TAMS). THE RELATIONSHIP BETWEEN CHRONIC INFLAMMATION AND HEPATOCARCINOGENESIS HAS BEEN THOROUGHLY INVESTIGATED OVER THE PAST DECADE; HOWEVER, SEVERAL ASPECTS OF THE ROLE OF TAMS IN HCC DEVELOPMENT ARE YET TO BE DETERMINED. IN RESPONSE TO CERTAIN STIMULI AND SIGNALING, MONOCYTES DIFFERENTIATE INTO MACROPHAGES WITH ANTITUMOR PROPERTIES, WHICH ARE CLASSIFIED AS M1-LIKE. ON THE OTHER HAND, UNDER DIFFERENT STIMULI AND SIGNALING, THE POLARIZATION OF MACROPHAGES SHIFTS TOWARDS AN M2-LIKE PHENOTYPE WITH A TUMOR PROMOTING CAPACITY. M2-LIKE MACROPHAGES DRIVE TUMOR GROWTH BOTH DIRECTLY AND INDIRECTLY, VIA THE SUPPRESSION OF CYTOTOXIC CELL POPULATIONS, INCLUDING CD8+ T CELLS AND NK CELLS. THE TUMOR MICROENVIRONMENT AFFECTS THE RESPONSE TO IMMUNOTHERAPIES. THEREFORE, AN ENHANCED UNDERSTANDING OF ITS IMMUNOBIOLOGY IS ESSENTIAL FOR THE DEVELOPMENT OF NEXT-GENERATION IMMUNOTHERAPIES. THE UTILIZATION OF VARIOUS MONOCYTE-CENTERED ANTICANCER TREATMENT MODALITIES HAS BEEN UNDER CLINICAL INVESTIGATION, SELECTIVELY TARGETING AND MODULATING THE PROCESSES OF MONOCYTE RECRUITMENT, ACTIVATION AND MIGRATION. THIS REVIEW SUMMARIZES THE CURRENT EVIDENCE ON THE ROLE OF TAMS IN HCC PATHOGENESIS AND PROGRESSION, AS WELL AS IN THEIR POTENTIAL INVOLVEMENT IN TUMOR THERAPY, SHEDDING LIGHT ON EMERGING ANTICANCER TREATMENT METHODS TARGETING MONOCYTES. 2022 18 3799 29 INTERPLAY BETWEEN INFLAMMATION AND EPIGENETIC CHANGES IN CANCER. IMMUNE RESPONSES CAN SUPPRESS TUMORIGENESIS, BUT ALSO CONTRIBUTE TO CANCER INITIATION AND PROGRESSION SUGGESTING A COMPLEX INTERACTION BETWEEN THE IMMUNE SYSTEM AND CANCER. EPIGENETIC ALTERATIONS, WHICH ARE HERITABLE CHANGES IN GENE EXPRESSION WITHOUT CHANGES TO THE DNA SEQUENCE, ALSO PLAY A ROLE IN CARCINOGENESIS THROUGH SILENCING EXPRESSION OF TUMOR SUPPRESSOR GENES AND ACTIVATING ONCOGENIC SIGNALING. INTERESTINGLY, EPITHELIAL CELLS AT SITES OF CHRONIC INFLAMMATION UNDERGO DNA METHYLATION ALTERATIONS THAT ARE SIMILAR TO THOSE PRESENT IN CANCER CELLS, SUGGESTING THAT INFLAMMATION MAY INITIATE CANCER-SPECIFIC EPIGENETIC CHANGES IN EPITHELIAL CELLS. FURTHERMORE, EPIGENETIC CHANGES OCCUR DURING IMMUNE CELL DIFFERENTIATION AND PARTICIPATE IN REGULATING THE IMMUNE RESPONSE, INCLUDING THE REGULATION OF INFLAMMATORY CYTOKINES. CANCER CELLS UTILIZE EPIGENETIC SILENCING OF IMMUNE-RELATED GENES TO EVADE THE IMMUNE RESPONSE. THIS CHAPTER WILL DETAIL THE INTERACTIONS BETWEEN INFLAMMATION AND EPIGENETICS IN TUMOR INITIATION, PROMOTION, AND IMMUNE EVASION AND HOW THESE CONNECTIONS ARE BEING LEVERAGED IN CANCER PREVENTION AND TREATMENT. 2016 19 6695 34 VARIANT GENE EXPRESSION AND ANTIGENIC VARIATION BY MALARIA PARASITES. MALARIA IS A SIGNIFICANT THREAT THROUGHOUT THE DEVELOPING WORLD. AMONG THE MOST FASCINATING ASPECTS OF THE PROTOZOAN PARASITES RESPONSIBLE FOR THIS DISEASE ARE THE METHODS THEY EMPLOY TO AVOID THE IMMUNE SYSTEM AND PERPETUATE CHRONIC INFECTIONS. KEY AMONG THESE IS ANTIGENIC VARIATION: BY SYSTEMATICALLY ALTERING ANTIGENS THAT ARE DISPLAYED TO THE HOST'S IMMUNE SYSTEM, THE PARASITE RENDERS THE ADAPTIVE IMMUNE RESPONSE INEFFECTIVE. FOR PLASMODIUM FALCIPARUM, THE SPECIES RESPONSIBLE FOR THE MOST SEVERE FORM OF HUMAN MALARIA, THIS PROCESS INVOLVES A COMPLICATED MOLECULAR MECHANISM THAT RESULTS IN CONTINUOUSLY CHANGING PATTERNS OF VARIANT-ANTIGEN-ENCODING GENE EXPRESSION. ALTHOUGH MANY FEATURES OF THIS PROCESS REMAIN OBSCURE, SIGNIFICANT PROGRESS HAS BEEN MADE IN RECENT YEARS TO DECIPHER VARIOUS MOLECULAR ASPECTS OF THE REGULATORY CASCADE THAT CAUSES CHRONIC INFECTION. 2017 20 3694 50 INFLAMMATORY COMPONENTS OF THE THYROID CANCER MICROENVIRONMENT: AN AVENUE FOR IDENTIFICATION OF NOVEL BIOMARKERS. THE INCIDENCE OF THYROID CANCER IN THE UNITED STATES IS ON THE RISE WITH AN APPRECIABLY HIGH DISEASE RECURRENCE RATE OF 20-30%. ANAPLASTIC THYROID CANCER (ATC), ALTHOUGH RARE IN OCCURRENCE, IS AN AGGRESSIVE FORM OF CANCER WITH LIMITED TREATMENT OPTIONS AND BLEAK CURE RATES. THIS CHAPTER USES DISCUSSIONS OF IN VITRO MODELS THAT ARE REPRESENTATIVE OF PAPILLARY, ANAPLASTIC, AND FOLLICULAR THYROID CANCER TO EVALUATE THE CROSSTALK BETWEEN SPECIFIC CELLS OF THE TUMOR MICROENVIRONMENT (TME), WHICH SERVES AS A HIGHLY HETEROGENEOUS REALM OF SIGNALING CASCADES AND METABOLISM THAT ARE ASSOCIATED WITH TUMORIGENESIS. THE CELLULAR CONSTITUENTS OF THE TME CARRY OUT VARYING CHARACTERISTIC IMMUNOMODULATORY FUNCTIONS THAT ARE DISCUSSED THROUGHOUT THIS CHAPTER. THE AFOREMENTIONED CELL TYPES INCLUDE CANCER-ASSOCIATED FIBROBLASTS (CAFS), ENDOTHELIAL CELLS (ECS), AND CANCER STEM CELLS (CSCS), AS WELL AS SPECIFIC IMMUNE CELLS, INCLUDING NATURAL KILLER (NK) CELLS, DENDRITIC CELLS (DCS), MAST CELLS, T REGULATORY (TREG) CELLS, CD8+ T CELLS, AND TUMOR-ASSOCIATED MACROPHAGES (TAMS). TAM-MEDIATED INFLAMMATION IS ASSOCIATED WITH A POOR PROGNOSIS OF THYROID CANCER, AND THE MOLECULAR BASIS OF THE CELLULAR CROSSTALK BETWEEN MACROPHAGES AND THYROID CANCER CELLS WITH RESPECT TO INDUCING A METASTATIC PHENOTYPE IS NOT YET KNOWN. THE DYNAMIC NATURE OF THE PHYSIOLOGICAL TRANSITION TO PATHOLOGICAL METASTATIC PHENOTYPES WHEN ESTABLISHING THE TME ENCOMPASSES A WIDE RANGE OF CHARACTERISTICS THAT ARE FURTHER EXPLORED WITHIN THIS CHAPTER, INCLUDING THE ROLES OF SOMATIC MUTATIONS AND EPIGENETIC ALTERATIONS THAT DRIVE THE GENETIC HETEROGENEITY OF CANCER CELLS, ALLOWING FOR SELECTIVE ADVANTAGES THAT AID IN THEIR PROLIFERATION. INDUCTION OF THESE PROLIFERATING CELLS IS TYPICALLY ACCOMPLISHED THROUGH INFLAMMATORY INDUCTION, WHEREBY CHRONIC INFLAMMATION SETS UP A CONSTANT PHYSIOLOGICAL STATE OF INFLAMMATORY CELL RECRUITMENT. THE SECRETIONS OF THESE INFLAMMATORY CELLS CAN ALTER THE GENETIC MAKEUP OF PROLIFERATING CELLS, WHICH CAN IN TURN, PROMOTE TUMOR GROWTH.THIS CHAPTER ALSO PRESENTS AN IN-DEPTH ANALYSIS OF MOLECULAR INTERACTIONS WITHIN THE TME, INCLUDING SECRETORY CYTOKINES AND EXOSOMES. SINCE THE EXOSOMAL CARGO OF A CELL IS A REFLECTION AND FINGERPRINT OF THE ORIGINATING PARENTAL CELLS, THE PROFILING OF EXOSOMAL MIRNA DERIVED FROM THYROID CANCER CELLS AND MACROPHAGES IN THE TME MAY SERVE AS AN IMPORTANT STEP IN BIOMARKER DISCOVERY. IDENTIFICATION OF A DISTINCT SET OF TUMOR SUPPRESSIVE MIRNAS DOWNREGULATED IN ATC-SECRETED EXOSOMES INDICATES THEIR ROLE IN THE REGULATION OF TUMOR SUPPRESSIVE GENES THAT MAY INCREASE THE METASTATIC PROPENSITY OF ATC. ADDITIONALLY, THE HIGH EXPRESSION OF PRO-INFLAMMATORY CYTOKINES IN STUDIES LOOKING AT THYROID CANCER AND ACTIVATED MACROPHAGE CONDITIONED MEDIA SUGGESTS THE EXISTENCE OF AN INFLAMMATORY TME IN THYROID CANCER. NEW FINDINGS ARE SUGGESTIVE OF THE PRESENCE OF A METASTATIC NICHE IN ATC TISSUES THAT IS INFLUENCED BY THYROID TUMOR MICROENVIRONMENT SECRETOME-INDUCED EPITHELIAL TO MESENCHYMAL TRANSITION (EMT), MEDIATED BY A RECIPROCAL INTERACTION BETWEEN THE PRO-INFLAMMATORY M1 MACROPHAGES AND THE THYROID CANCER CELLS. THUS, TARGETING THE METASTATIC THYROID CARCINOMA MICROENVIRONMENT COULD OFFER POTENTIAL THERAPEUTIC BENEFITS AND SHOULD BE EXPLORED FURTHER IN PRECLINICAL AND TRANSLATIONAL MODELS OF HUMAN METASTATIC THYROID CANCER. 2021